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Subcellular spatio-temporal intravital kinetics of aflatoxin B₁ and ochratoxin A in liver and kidneySubcellular spatio-temporal intravital kinetics of aflatoxin B1 and ochratoxin A in liver and kidney

Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Ghallab, Ahmed;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Hassan, Reham;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Myllys, Maiju;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Albrecht, Wiebke;
Affiliation
Institute of Computer Science, Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, Leipzig, Germany
Friebel, Adrian;
Affiliation
Institute of Computer Science, Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, Leipzig, Germany
Hoehme, Stefan;
Affiliation
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, Germany
Hofmann, Ute;
Affiliation
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
Seddek, Abdel-latif;
Affiliation
German Federal Institute for Risk Assessment (BfR), Department 5 Food Safety, Unit 51 Effect-based Analytics and Toxicogenomics, Germany
Braeuning, Albert;
Affiliation
Institute of Systems Medicine with Focus on Organ Interactions, University Hospital RWTH Aachen, Pauwelsstr. 19, Aachen, Germany
Kuepfer, Lars;
Affiliation
Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstr. 45, Münster, Germany
Cramer, Benedikt;
Affiliation
Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstr. 45, Münster, Germany
Humpf, Hans-Ulrich;
Affiliation
Institute of Systems Medicine with Focus on Organ Interactions, University Hospital RWTH Aachen, Pauwelsstr. 19, Aachen, Germany
Boor, Peter;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Degen, Gisela H.;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, Dortmund, Germany
Hengstler, Jan G.

Local accumulation of xenobiotics in human and animal tissues may cause adverse effects. Large differences in their concentrations may exist between individual cell types, often due to the expression of specific uptake and export carriers. Here we established a two-photon microscopy-based technique for spatio-temporal detection of the distribution of mycotoxins in intact kidneys and livers of anesthetized mice with subcellular resolution. The mycotoxins ochratoxin A (OTA, 10 mg/kg b.w.) and aflatoxin B₁ (AFB₁, 1.5 mg/kg b.w.), which both show blue auto-fluorescence, were analyzed after intravenous bolus injections. Within seconds after administration, OTA was filtered by glomeruli, and enriched in distal tubular epithelial cells (dTEC). A striking feature of AFB₁ toxicokinetics was its very rapid uptake from sinusoidal blood into hepatocytes (t₁/₂ ~ 4 min) and excretion into bile canaliculi. Interestingly, AFB₁ was enriched in the nuclei of hepatocytes with zonal differences in clearance. In the cytoplasm of pericentral hepatocytes, the half-life (t₁/₂~ 63 min) was much longer compared to periportal hepatocytes of the same lobules (t₁/₂ ~ 9 min). In addition, nuclear AFB₁ from periportal hepatocytes cleared faster compared to the pericentral region. These local differences in AFB₁ clearance may be due to the pericentral expression of cytochrome P450 enzymes that activate AFB₁ to protein- and DNA-binding metabolites. In conclusion, the present study shows that large spatio-temporal concentration differences exist within the same tissues and its analysis may provide valuable additional information to conventional toxicokinetic studies.

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